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Exendin-4 promotes pancreatic β-cell proliferation via inhibiting the expression of Wnt5a

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Abstract

Exendin-4, a glucagon-like peptide-1 receptor agonist, is currently regarded as an effective therapeutic strategy for type-2 diabetes. Previous studies indicated that exendin-4 promoted β cell proliferation. However, the underlying mechanisms remain largely unknown. Recently it was reported that exendin-4 promoted pancreatic β cell proliferation by regulating the expression level of Wnt4. The present study was designed to investigate whether other Wnt isoforms take part in accommodation of β-cell proliferation. We found that exendin-4 promotes the proliferation and suppresses the expression of Wnt5a in INS-1 cell line and C57Bl/6 mouse pancreatic β-cells. Further mechanistic study demonstrated that exendin-4 promoted INS-1 cell proliferation partly through down-regulating the expression of Wnt5a. Furthermore, Wnt5a could induce the activation of calmodulin-dependent protein kinase II in INS-1 cells, thereby decreasing the cellular stable β-catenin and its nuclear translocation, and finally reduce the expression of cyclin D1. In addition, we also found that both of the receptors (Frz-2 and Ror-2) mediated the effect of Wnt5a on β cell line INS-1 proliferation. Taken together, this study suggests that Wnt5a plays a critical role in exendin-4-induced β-cell proliferation, indicating that Wnt5a might be a novel regulator in counterbalance of β cell mass.

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Funding

This research was supported by grants from the Industrial Technology Research and Development funding projects, Guangdong Province (No. 2012A030400006); Guangzhou Municipal Science and Technology special fund (No. 1346000270); Medical and Health Major projects, Zhongshan (No.2016B1001); Doctoral Fund of Ministry of Education, China (No. 20130171110067); Sun Yat-sen University Clinical Research 5010 Program; Special Fund for Public Service of Ministry of Health, China (No. 201502007).

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  1. Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Xinger Wu, Weiwei Liang, Hongyu Guan, Juan Liu, Liehua Liu, Hai Li, Xiaoying He, Jing Zheng, Jie Chen, Xiaopei Cao & Yanbing Li

  2. Southern Medical University, Guangzhou, China

    Xinger Wu

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  1. Xinger Wu
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Xinger Wu and Weiwei Liang contribute equally to this work.

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Wu, X., Liang, W., Guan, H. et al. Exendin-4 promotes pancreatic β-cell proliferation via inhibiting the expression of Wnt5a. Endocrine 55, 398–409 (2017). https://doi.org/10.1007/s12020-016-1160-x

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